A central problem in neurobiology concerns the molecular mechanisms underlying enduring modifications of synaptic function and structure. Insights into these mechanisms will have broad relevance to human cognition and neuropsychiatric disease. Enduring forms of synaptic plasticity and memory require new protein synthesis, but little is known about the underlying regulatory mechanisms. The ERK/MAPK and mTOR signaling pathways have been implicated in synaptic plasticity, but their possible contribution to the protein synthesis-dependent processes underlying long-term synaptic plasticity and memory have not been examined. In the present application, conditional expression of a dominant-negative form of MEK1 in the post-natal murine forebrain is shown to inhibit ERK activation and cause selective deficits in hippocampal memory consolidation and the translation dependent, transcription independent phase of hippocampal LLTP. Translational studies in hippocampal neurons demonstrate that ERK inhibition blocks neuronal activity induced protein synthesis in a manner independent of cis-acting mRNA sequences. These results suggest a crucial role for translational control by ERK signaling in long-lasting forms of synaptic plasticity and memory. To extend these findings, the following hypotheses will be tested: 1) The ERK and mTOR pathways regulate protein synthesis in response to neuronal activity through phosphorylation of key components of the translational machinery; 2) ERK-dependent translational induction is required for the establishment of protein synthesis-dependent bidirectional synaptic plasticity, i.e. L-LTP and L LTD; 3) ERK dependent translational control plays an important role in the structural plasticity of dendritic spines. The career development program will be enhanced by collaborations with two senior investigators with expertise in the proposed investigations, Mark Bear and Morgan Sheng at MIT, and by attendance and presentation of results at local seminars and international conferences. Clinical work on memory disorders will complement the proposed research. The Neurology Department at MGH provides a rich and diverse scientific environment for the proposed career development plan, which will facilitate the establishment of a research program devoted to understanding the mechanisms of human cognition and cognitive disorders.